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Open Access DOI: 10.32474/AOICS.2018.03.000156

ISSN: 2637-4609 Research Article

Preparation of Morphine Derivatives Using Ionic Liquids

Sureshbabu Jayachandra, Madhuresh Kumar Sethi*, Sanjay Mahajan, Kunwar Sanjeev Singh, Bhairaiah Mara and
Purbita Chakraborty
Mylan Laboratories Ltd. ANRICH Industrial Estate, India
Received: May 25, 2018; Published: June 11, 2018

*Corresponding author: Madhuresh Kumar Sethi, R and D, Mylan Laboratories Ltd, A ANRICH Industrial Estate, Bollaram, Sangareddy,
Telangana, India, Email:

Abstract
Dextromethorphan, an anti tussive drug belongs to the morphinan family, and is mostly available in the market as a combination
therapy. Most of the reported preparation procedures involve the use of racemic starting materials that give lower yields. (S)- Octa
base is one of the key starting raw materials used in our process and this easy, convenient and eco-friendly preparation (single
step) is reported in this manuscript. This drug, Dextromethorphan is produced in large volumes annually (> 150 tons/year). Most
reported synthetic procedures make use of huge amounts of volatile organic solvents which are hazardous for environment. This
will be a major issue in the near future. To overcome this problem, we have tried using Ionic liquid as a solvent in the preparation
and successfully arrived at best results, thereby decreasing the use of organic volatile solvents.

Keywords: Dextromethorphan; Morphine derivatives; Alkaloids; Formylation; Ionic liquid

Introduction
Dextromethorphan bound to an ion-exchange resin based on
Dextromethorphan, a drug of the morphinan family, is having polystyrene sulfonic acid (Picture 1).
tranquilizing, dissociative, and restorative properties (especially at
higher doses). It is a cough suppressant (ANTI-TUSSIVE) in several
over-the-counter cold and cough medicines including generic labels
and store brands, Benylin, Mucinex, Camydex 20 tablets, Robitussin,
NyQuil, Vicks, Delsym, TheraFlu, Cheracol D, and others. It has also
found plentiful other uses in medication, extending from analgesic
effect to psychological submissions useful in the treatment of
addiction. It is sold in syrup, capsule, and lozenge forms. In its
unadulterated form, Dextromethorphan ensues as a white powder.
Currently, Dextromethorphan is not registered in the Schedules of
the United Nations 1961 Convention on Narcotic Drug [1]. Picture 1: Chemical structure of Dextromethorphan Hydro
bromide.
Dextromethorphan is the dextrorotatory enantiomer of
levomethorphan, which is the methyl ether of levorphanol, both Mechanism of Action
opioid analgesics. It’s IUPAC name is (+)-3-methoxy-17-methyl-9α, Dextromethorphan is a synthetic compound and acts as a
13α, 14α-morphinan. It occurs as an odorless, opalescent white dissociative anesthetic when taken in higher doses. Its mechanism
powder. It is freely soluble in chloroform and insoluble in water; of action is via multiple effects, plus actions as a nonselective
the hydro bromide salt is water-soluble up to 1.5g/100mL at 25 serotonin reuptake inhibitor and a sigma-1 receptor agonist [2].
°C. It is usually accessible as the monohydrated hydro bromide Dextromethorphan and its major metabolite, Dextrorphan, also
salt. However, some newer extended-release formulations contain act as NMDA receptor antagonist at high doses, which produces

Citation: Sureshbabu J, Madhuresh KS, Sanjay M, Kunwar SS, Bhairaiah M, Purbita C. Preparation of Morphine Derivatives Using Ionic Liquids.
Arc Org Inorg Chem Sci 3(2)- 2018. AOICS.MS.ID.000156. DOI: 10.32474/AOICS.2018.03.000156. 318
Arc Org Inorg Chem Sci Copyrights@ Madhuresh K S, et al.

effects similar to other dissociative anesthetics such as ketamine
and phencyclidine [3]. The metabolic pathway continues from
dextrorphan to 3-methoxymorphinan to 3-hydroxymorphinan
(Figure 1) [4].
chemicals that are easy to handle and can provide higher yields as
well as purity, it has been found that the critical step of Grewe’s
cyclization is reported in a paper titled, ‘A Novel synthesis of
substituted 1-benzyloctahydroisoquinolines by acid-catalyzed
cyclization of N-[2-(Cyclohex-1-enyl]-N-styryl formamides’ [5]
(Scheme 3).

Figure 1: Explains the metabolic pathway of the drug

Scheme 2: Explains another reported procedure, where
Dextromethorphan.
alternate reagents like KBH4, R-ibuprofen and AlCl3 have
In one of the reported processes for the preparation of been used to refine the existing method of preparation of
morphinan alkaloids, racemic hydroxy N- methyl morphinan Dextromethorphan.
is used as a starting material, an optically inactive isomer and is
treated with tartaric acid for resolution to obtain selective one
isomer (+) of morphinan. (PATENT- US2676177 (Roche, 1954, CH-
prior.1949)) (Scheme 1).

Scheme 3: Explains a reported procedure involving the

preparation of Dextromethorphan that involves Grewe`s
cyclization.

Scheme 1: This scheme explains the reported procedure

that uses a racemic hydroxy N- methyl morphinan as a
starting material along with the use of solvents.

In a similar procedure reported in PATENT- CN102977021 A,

Method for preparation of Dextromethorphan hydro bromide By
Cui, Dapeng et al From Faming Zhuanli Shenqing, 102977021, 20
Mar 2013, Raney Nickel as a reducing agent is replaced by KBH4,
thus, reducing the cost. Also, resolution is done with R-ibuprofen
for the first time. Another advantage is the use of AlCl3 is adopted to
replace H3PO4 to cyclize. Overall, it is a low cost, moderate reaction Scheme 4: Explains a reported procedure of Dextrometho-
conditions, easy in operation and suitable for industrial production rphan preparation, where formylation was done before
the cyclization step to improve the yield.
(Scheme 2).

Further, in the search for better preparation methods, which According to this paper, no cyclization of enamide was
is easier, lesser preparation steps, cost effective, and also using observed with Lewis acid catalyst (AlCl3, AlEtCl2, TiCl4), Two

Citation: Sureshbabu J, Madhuresh KS, Sanjay M, Kunwar SS, Bhairaiah M, Purbita C. Preparation of Morphine Derivatives Using Ionic Liquids.
Arc Org Inorg Chem Sci 3(2)- 2018. AOICS.MS.ID.000156. DOI: 10.32474/AOICS.2018.03.000156. 319
Arc Org Inorg Chem Sci Copyrights@ Madhuresh K S, et al.

equivalents of BF3-Et2O was used, and complete conversion m/z (M+H+) - 286
was observed. In all cyclization reactions, a side product is
NMR chemical shift values tabulated below (Table 1) and
formed that is more polar than the octa hydroisoquinolines and
(Picture 2).
N-formyl octa hydroisoquinolines synthesized from N-formyl-
2-phenylethylamines and benzaldehyde. Also, reduction of Table 1: s- singlet, m-multiplet, br-broad.
N-formaldehyde to N-methylated was done using LiAlH4. While
going through literature, it was found that formylation before Position 1
H d (ppm) Multiplicity 13
C DEPT

cyclisation avoids ether cleavage as a side reaction and higher yields 1 2H 1.60-2.24 m 29.43 CH2
were obtained than without N-substitution or N-methylation. In 2 2H 1.60-2.24 m 22.39 CH2
this patent, purification/resolution was done using the formation 3 2H 1.60-2.24 m 22.51 CH2
of Brucine salt (US3634429 (Jan 11, 1972) Morphinan derivatives 4 2H 1.60-2.24 m 26.91 CH2
and preparation there of (Scheme 4). 5 - - - 130.15 -

Experimental and Results 6 1H 4.07-4.13 m 54.69 CH

7Ha 1H 2.85-3.09 m 32.39 CH2
All the above-mentioned processes involve the use of solvents.
So, in the existent investigation, an endeavor is explored to develop 7Hb 1h 2.78-3.82 m

an alternate process wherein use of solvents can be avoided in the 8 2H 1.60-2.24 m 29.15 CH2
synthesis of Dextromethorphan (Scheme 5). 9 - - - 127.49 -
10Ha 1H 2.58-2.74 m 36.66 CH2
10Hb 1H 2.85-3.09 m
11 3H 3.71 s 54.74 CH3
12 - - - 128.38 -
13,13’ 2H 7.03-7.08 m 130.21 CH
14,14’ 2H 6.77-6.86 m 113.56 CH
15 - - - 157.78 -
16 1H 7.34 br, s 160.08 CH

Scheme 5: Explains a greener preparation of Dextrometho-

rphan using an Ionic Liquid.

Preparation of Dextromethorphan Hydrobromide using

1-butyl-3-methyl imidazolium acetate (Ionic liquid) as a
solvent Picture 2.

I-step: b) Stage-IB: In another flask, charge Ortho phosphoric acid

a) Stage-IA: In a flask, charge 1-butyl-3-methyl imidazolium
acetate under nitrogen atmosphere. Charge (S)-Octa base under
nitrogen atmosphere. Cool if required under nitrogen atmosphere.
Charge Sodium methoxide solution in methanol under nitrogen
atmosphere. Charge Methyl formate. Raise the temperature of the
reaction mass to little reflux by using hot water not more than
55oC. Stir and maintain the reaction mass till reaction complies (2
hours). Concentrate the reaction mass u/v (Capacity of vacuum
pump should be > 700 mm/Hg) till almost no solvent distills. To
the concentrated reaction mass, charge toluene under nitrogen
atmosphere and water extraction is done. The extracted toluene
layer was concentrated to give N-Formyl octa base and is used as
such.
(~ 85.0 % w/w). Charge Toluene and Raise the temperature of the
reaction mass. Reflux and maintain over Dean stark apparatus to
remove water azeotropically. Cool the reaction mass under nitrogen
atmosphere and Charge Phosphorus pentoxide under nitrogen
atmosphere. Reaction is highly exothermic. Charge 1-butyl-3-methyl
imidazolium acetate. Slowly add N-formyl octa base and Raise the
temperature of the reaction mass under nitrogen atmosphere.
Stir and maintain the reaction mass at 65-70oC under nitrogen
atmosphere till reaction complies. Concentrate the reaction mass
under vacuum to remove toluene. To the concentrated mass, charge
ethyl acetate under nitrogen atmosphere and stir. In another flask,
charge water, Cool. Charge ethyl acetate reaction mixture reaction
mass in to chilled water. Stir, settle and separate the layers. Repeat

Citation: Sureshbabu J, Madhuresh KS, Sanjay M, Kunwar SS, Bhairaiah M, Purbita C. Preparation of Morphine Derivatives Using Ionic Liquids.
Arc Org Inorg Chem Sci 3(2)- 2018. AOICS.MS.ID.000156. DOI: 10.32474/AOICS.2018.03.000156. 320
Arc Org Inorg Chem Sci Copyrights@ Madhuresh K S, et al.

for back extraction. Wash the organic layer with water again Stir and maintain the reaction mass till reaction complies (~15
and then a wash of 7% sodium bicarbonate solution is given. hours). Concentrate the reaction mass u/v. To the concentrate
Concentrate the organic layer u/v till almost no solvent distills. mass, charge toluene under nitrogen atmosphere and water
Degas the concentrate u/v to remove traces of solvents. workup is done. The extracted toluene layer was concentrated to
give N-Nordextromethorphan (Stage-IC).
m/z (M+H+) - 286
m/z (M+H+) - 258
NMR chemical shift values tabulated below (Table 2) and
(Picture 3) NMR chemical shift values tabulated below (Table 3) and
(Picture 4):
Table 2: s- singlet, m-multiplet, br-broad.
Table 3: s- Singlet, m-multiplet, br-broad.
Position 1
H d (ppm) J(Hz)1 13
C DEPT
1 2H 0.89-1.66 m 35.65 CH2 Position 1
H d (ppm) J (Hz)1 13
C DEPT
2 2H 0.89-1.66 m 21.64 CH2 1Ha 1H 1.38-1.50
m 36.50 CH2
25.65- 1Hb 1H 2.27-2.52
3 2H 0.89-1.66 m CH2
25.89
2Ha 1H 1.15-1.34
4 2H 0.89-1.66 m 30.31 CH2 m 21.82 CH2
2Hb 1H 1.38-1.50
5 1H 2.63-2.76 - 44.26 CH
3Ha 1H 0.87-0.97
6 1H 3.02-3.22 m 52.12 CH m 26.46 CH2
3Hb 1H 1.15-1.34
7Ha 1H 2.36-2.57 m 40.09 CH2
4 2H 1.15-1.34 m 26.28 CH2
7Hb 1H
5 1H 1.56-1.67 m 45.27 CH2
8 2H 0.89-1.66 m 34.06 CH2
6 1H 2.84-2.99 m 50.18 CH
9 - - - 41.45 -
7 2H 2.27-2.52 m 42.39 CH2
10 2H 2.18-2.3 m 31.77 CH2
8Ha 1H 1.15-1.34 m 38.56 CH2
11 - - - 128.82 -
8Hb 1H 1.56-1.67
12 - - - 125.22 -
9 - - - 37.92 -
13 1H 7.00-7.06 m 128.11 CH
10Ha 1H 2.63 d (17.4) 33.05 CH2
110.77-
14,14’ 2H 6.72-6.84 m CH 10Hb 1H 2.84-2.99 m
111.53
128.87- 11 - - - 141.28 -
15 - - - -
128.88 12 - - - 128.85 -
16 1H 7.95-8.11 s 160.54 CH 13 1H 7.01 d (8.4) 128.27 CH
17 3H 3.73 s 54.81 CH3 14 1H 6.67-6.75 m 110.77 CH
15 - - - 157.70 -
16 1H 6.67-6.75 m 110.58 -
17 3H 3.70 s 54.77 CH3
NH 1H 2.27-2.52 br - -

Picture 3.

c) Stage-IC: To the concentrate mass, charge 1-butyl-

3-methyl imidazolium acetate and methanol under nitrogen
atmosphere. Stir and slowly add sodium hydroxide solution Pre-
Cooled ~15oC (Prepare by using 109 g Sodium hydroxide dissolved Picture 4.
in 200ml Water). Raise the temperature of the reaction mass and

Citation: Sureshbabu J, Madhuresh KS, Sanjay M, Kunwar SS, Bhairaiah M, Purbita C. Preparation of Morphine Derivatives Using Ionic Liquids.
Arc Org Inorg Chem Sci 3(2)- 2018. AOICS.MS.ID.000156. DOI: 10.32474/AOICS.2018.03.000156. 321
Arc Org Inorg Chem Sci Copyrights@ Madhuresh K S, et al.

d) Stage-ID: To the mixture of1-butyl-3-methyl imidazolium

acetate and N-Nordextromethorphan (Stage-IC), slowly add Formic
acid solution (Prepare by using 32.1g Formic acid diluted with 5.7ml
water). Charge Formaldehyde solution. Raise the temperature of the
reaction mass and Stir and maintain the reaction mass till reaction
complies (~2 hours). After the reaction is complete, Charge water
and cool the reaction mass if required and then slowly add sodium
hydroxide solution Pre-cool (< 15 oC) (Prepared by using 28.0g
Sodium hydroxide dissolved in 140ml water), extracted the product
into toluene, again charge water, cool, and slowly add Hydrobromic
acid. Raise the temperature of the reaction mass to 70-80 oC and
Stir and maintain to get clear solution. The organic and aqueous
layers separated. Cool the Aqueous layer under stirring to get Picture 5.
precipitate and further cooled to 3-6 oC and wash with pre-chilled
a) 1H-1H coupling constants.
water. Dry the solid under vacuum, to get Dextromethorphan hydro
bromide. Discussion
m/z (M+H+) - 272 As of today, chemical manufacturing process of APIs in
pharmaceutical industry is handicapped without the use of
NMR chemical shift values tabulated below (Table 4) and
chemical solvents. However, it is a scientifically known fact that
(Picture 5):
solvents are dangerously damaging chemical entities, mainly of the
Table 4: s- Singlet, d- doublet, m-multiplet, br-broad. following reasons:

Position 1
H (ppm) J(Hz)1 13
C DEPT a) Volatile nature of solvents.
1Ha 1H 1.43-1.64 b) Storage and handling risks.
m 38.51 CH2
1Hb 1H 2.44-2.50
c) Usage requirements in large scale.
2Ha 1H 1.24-1.37
m 21.38 CH2
2Hb 1H 1.43-1.64 Apart from their handling risks to human beings, they also
3Ha 1H 1.43-1.64 cause significant saturation in chemical pollution levels in the
m 22.65 CH2 environment; there has been constant research going-on in
3Hb 1H 1.11-1.19
4Ha 1H 1.42-1.64
academic field as well as industries to find their suitable alternative
m 25.30 CH2 [6].
4Hb 1H 1.77-1.88
5 1H 1.77-1.88 m 41.40 CH Ionic liquids are one such alternative that has been found useful
6 1H 3.62 m 58.82 CH to substitute the commonly used bench solvents. Other than their
7Ha 1H 2.44 s obvious “solvent” property that have been discussed in various
46.95 CH2 publications [7-10], they have also been found to catalyze certain
7Hb 1H 3.11-3.20 m
type of reactions in which they participate [11-13]. Moreover, their
8Ha 1H 1.43-1.64
m 34.72 CH2 complete recovery from the reaction is an easy job when juxtaposed
8Hb 1H 2.01-2.05
with their volatile solvent counterparts. For this reason, an ionic
9 - - - 35.37 -
liquid can be re-cycled for multiple batches of reactions.
10Ha 1H 2.93-3.05
m 25.18 CH2
10Hb 1H 3.11-3.20 Another unique property of ionic liquids is that they can be
“tailor-made” to suit specific reaction types by playing around with
11 - - - 138.63 -
the cation and anion part of them. They are called as “task-specific
12 - - - 129.27 -
ionic liquids”. These tailored [14] and specially synthesized ionic
13 1H 7.14 d (9.3) 125.88 CH
liquids have more scope of their application in a chemical reaction
110.55,
14,14’ 2H 6.81-6.84 m CH than just acting as a green solvent.
112.07
15 - - - 158.44 - Conclusion
16 3H 2.81 s 40.06 CH3
A simple, efficient, eco-friendly synthetic route is developed
17 3H 3.73 s 55.04 CH3 involving the single-step synthesis of Dextromethorphan
18 1H 9.78 br - - Hydrobromide that is high on convenience and also a cost-effective

Citation: Sureshbabu J, Madhuresh KS, Sanjay M, Kunwar SS, Bhairaiah M, Purbita C. Preparation of Morphine Derivatives Using Ionic Liquids.
Arc Org Inorg Chem Sci 3(2)- 2018. AOICS.MS.ID.000156. DOI: 10.32474/AOICS.2018.03.000156. 322
Arc Org Inorg Chem Sci Copyrights@ Madhuresh K S, et al.

procedure. This process is best suitable for the preparation of
Dextromethorphan Hydrobromide and is scalable in plant. This
synthetic route using an ionic liquid adapts a cleaner chemistry
that assures both risk-free handling and reduced environmental
pollution, when scaled-up.
Acknowledgement
Our group would like to thank the Department of Scientific and
Industrial Research India, Dr. Hari Babu (COO Mylan), Sanjeev Sethi
(Chief Scientific Officer Mylan Inc ); Dr Abhijit Deshmukh (Head of
Global OSD Scientific Affairs); Dr Yasir Rawjee {Head-Global API
(Active Pharmaceutical Ingredients)}, Dr Sureshbabu Jayachandra
(Head of Chemical Research) Mr Manoj Pananchukunnath (Head
of Global Injectables Scientific Affairs, Product Development) Dr.
Suryanarayana Mulukutla (Head Analytical Dept MLL API R & D) as
well as analytical development team of Mylan Laboratories Limited
for their encouragement and support. We would also like to thank
Dr Narahari Ambati (AGC- India IP) & his Intellectual property team
for their support.
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1. Reference Tables: Description and Solubility-D.

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Citation: Sureshbabu J, Madhuresh KS, Sanjay M, Kunwar SS, Bhairaiah M, Purbita C. Preparation of Morphine Derivatives Using Ionic Liquids.
Arc Org Inorg Chem Sci 3(2)- 2018. AOICS.MS.ID.000156. DOI: 10.32474/AOICS.2018.03.000156. 323